Long-term objectives specific aims and clinical significance Ovarian cancer is one of the deadliest types of cancers. The lack of effective screening strategy and lack of symptoms result in frequent late diagnosis and poor patient survival. The goal of this project is to enhance our understanding of the factors that control progression of ovarian cancer, with a particular focus on the causes for the elevated risk and the worse prognosis of ovarian cancer in postmenopausal women. Our working hypothesis is that elevated levels of the gonadotropin hormones LH and FSH affect tumor progression indirectly by promoting tumor-stroma interaction, increasing tumor cell adhesion and angiogenesis. In that framework we will study three specific aims. The first aim will be to evaluate the impact of the recruitment and activation of fibroblasts in tumors and the potential for utilizing this process for tumor detection and therapeutic intervention. Over the last years we demonstrated that fibroblast recruitment and their activation to form myofibroblast are critical for progression of ovarian tumors. The massive recruitment and activation of fibroblasts opens the exciting possibility for development of a cell based strategy for tumor detection and for image guided drug delivery. In contrast with other cell based therapeutic approaches, fibroblasts are abundant and easy to derive in large quantities. The second aim will be to reveal the mechanisms controlling adherent invasive progression versus non-adherent ascitic growth in ovarian cancer. The dual mode of growth of ovarian carcinoma as ascitic fluid and as adherent implants on the peritoneal surface creates a unique mode of selective pressure. We will develop a model for adherent and non-adherent tumor growth, along with tools for non-invasive detection of these growth patterns, allowing to check the implications of this growth pattern on the regulation of tumor angiogenesis. Finally, the third aim will reveal the mechanisms by which the outer ovarian epithelium can maintain the viability of tumor cells thereby supporting the early stages of tumor development. Ovarian cancer was linked to ovulation, but the other hand, ovarian cancer is rare in young women, and is significantly more prevalent in postmenopausal women. We aim to reveal the biological mechanism underlying these seemingly contradictory risk factors. To achieve these aims, advanced non-invasive multimodality imaging tools will be developed and will be applied for monitoring the spatial-temporal patterns of tumor progression and tumor stroma interactions. These studies may help explain the basis for the effects of ovulation on one hand and menopause on the other in the etiology of ovarian cancer. PUBLIC HEALTH RELEVANCE: Ovarian cancer, the most deadly gynecological cancer, occurs predominantly in postmenopausal women, in which the ovary is no longer reproductively active. The goal of this project is to reveal why this disease is more frequent and more aggressive in older women. In particular, we aim to reveal how the hormonal changes that occur at menopause affect the progression of ovarian cancer by affecting the interaction of tumors with their environment. Imaging tools are developed to help visualize tumor cell death, the growth of tumor blood and lymphatic vessels and the participation of normal cells in tumor growth.